[8+2]formal cycloaddition reactions of tropones with azlactones under bronsted acid catalysis and synthesis of α-(2-tropyl), α-alkyl α-amino acids

Article abstract of DOI:10.1002/ejoc.201301774

The reaction of tropones with azlactones catalyzed by Bronsted acids affords a variety of dihydro-2H-cyclohepta[b]furan derivatives, corresponding to a formal [8+2] cycloaddition process. They can easily be opened by nucleophiles to afford a new type of α,α-disubstituted α-amino acid (or peptide) containing seven-membered rings at the quaternary position. The reaction of tropones with azlactones catalyzed by Bronsted acids affords a variety of dihydro-2H-cyclohepta[b]furan derivatives, corresponding to a formal [8+2] cycloaddition process. They can be easily opened by nucleophiles to afford a new type of α,α-disubstituted α-amino acid (or peptide) containing seven-membered rings at the quaternary position. Copyright

Full text of DOI:10.1002/ejoc.201301774

FULL PAPER
DOI: 10.1002/ejoc.201301774
[8+2] Formal Cycloaddition Reactions of Tropones with Azlactones under
Brønsted Acid Catalysis and Synthesis of α-(2-Tropyl), α-Alkyl α-Amino Acids
Francisco Esteban,[a] Ricardo Alfaro,[a] Francisco Yuste,[a] Alejandro Parra,[a]
José Luis García Ruano,*[a] and José Alemán*[a]
Keywords: Amino acids / Tropones / Cycloaddition / Brønsted acids catalysis / Heterocycles
The reaction of tropones with azlactones catalyzed by
afford a new type of α,α-disubstituted α-amino acid (or pept-
Brønsted acids affords a variety of dihydro-2H-cyclohepta-
ide) containing seven-membered rings at the quaternary po-
[b]furan derivatives, corresponding to a formal [8+2] cycload- sition.
dition process. They can easily be opened by nucleophiles to
Introduction
addition processes (Scheme 1, equation a). One of the most
The nonbenzenoid aromatic structure of tropones and
troponoids has attracted the attention of chemists in the
last decades from a theoretical and synthetic point of
view.[1] These structures have been found and used in the
total synthesis of natural products,[2] and their behavior in
cycloaddition reactions has been widely studied as an ido-
neous π system for the investigation of the competition be-
tween different types of reactions.[3] Other aspects concern-
ing their reactivity, such as nucleophilic additions, have also
been studied,[4] and most of them have involved 1,8-
interesting reactions of the tropones occurs with reagents
that simultaneously contain nucleophilic and electrophilic
centers. They are tandem processes involving an initial nu-
cleophilic attack at C-2 of the tropone ring (1,8-addition)
followed by an intramolecular reaction of the resulting
enolate with the electrophilic center of the reagent
(Scheme 1, equation b). Precursors of different 1,3-dipoles
have been used in these reactions to afford bicyclic struc-
tures that formally correspond to [8+2][5] and [6+3][6] cyclo-
Scheme 1. Different reactivities of tropone derivatives.
additions processes,[7] but the use of azlactones in this type
of reaction has never been explored.
At this point, we hypothesized about the reactions of
tropones with azlactones because they are stable com-
pounds that exhibit dual electrophilic (carbonylic carbon
atom) and nucleophilic (C-2 or C-4) behavior. The C-4
[a] Departmento de Química Orgánica (módulo 1), Facultad de
Ciencias, Universidad Autónoma de Madrid,
Cantoblanco, 28049 Madrid, Spain
E-mail: jose.aleman@uam.es
www.uam.es/JLGR
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301774.
Eur. J. Org. Chem. 2014, 1395–1400
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1395

J. L. G. Ruano, J. Alemán et al.
FULL PAPER
nucleophilic attack of the azlactone at the electrophilic C-2
Results of Scheme 2 indicate that the acidic catalysis is
of the tropone ring (1,8-nucleophilic addition) would gener- more efficient (better reactivity and stereoselectivity con-
ate the enolate I, which facilitates the intramolecular open- trol), which prompted us to optimize these reactions
ing of the oxazolone ring by the enolate oxygen atom to (Table 1). We first found that the reaction of 1A with 2a
afford lactones II (a formal [8+2] cycloaddition reaction). occurred in 5 h in the presence of 5 mol-% of dpp without
These lactones would be interesting precursors of N-pro- a significant effect on the diastereomeric ratio of 3Aa and
tected quaternary amino acid derivatives, which could 3ЈAa (70:30; Table 1, Entry 1). Then, we studied the influ-
eventually be incorporated into peptide chains.[8] Moreover, ence of other Brønsted acids (5 mol-%) on the reaction
the peptide would contain an unusual seven-membered ring course. Complete conversion was also observed after 5 h
located at C-α, easily obtained in reactions with oxygenated by using (+)-camphorsulfonic acid and trifluoroacetic acid
or nitrogenated nucleophiles, that could be used to intro- (TFA; Table 1, Entries 4 and 5), whereas lower conversions
duce other functionalities into the peptides. The importance were obtained in the presence of BzOH and p-toluenesulf-
of quaternary amino acids and the peptides containing onic acid (TsOH; Table 1, Entries 2 and 3). As the best
them[9] justifies the search for new synthetic methods, a field diastereomeric ratio (dr) was obtained with TFA (77:23;
in which azlactones have played a relevant role.[10] In this Table 1, Entry 5), this acid was used for further optimiza-
work, we report the results obtained in the reaction of tro- tion. Diastereoselectivity and reactivity were influenced by
pones with azlactones catalyzed by Brønsted acids and the the solvent. Thus, the conversions were not complete after
use of the resulting lactones in the synthesis of new α,α- 5 h in tetrahydrofuran (THF) and CHCl3, and lower dia-
disubstituted α-amino acids bearing seven-membered rings stereoselectivities than those in CH2Cl2 were obtained
at the quaternary center.
(Table 1, Entries 6 and 7). In toluene and p-xylene, com-
plete conversion and a better dr were obtained (Table 1, En-
tries 8 and 9). The use of a lower amount of catalyst (1 mol-
Results and Discussion
We first studied the reaction of tropone (1A) with the
azlactone 2a in CH2Cl2. After several hours at room tem-
perature, no reaction occurred (Scheme 2), but in the pres-
ence of catalytic amounts of acids or bases (which presum-
ably activate the tropone or the azlactone, respectively),
mixtures of the bicyclic lactones 3Aa and 3ЈAa are found.
Thus, under diphenylphosphoric acid catalysis (dpp,
10 mol-%), the reaction gave full conversion to a 75:25 mix-
ture of 3Aa/3ЈAa after 1 h at room temp. (Scheme 2). How-
ever, in the presence of Et3N (10 mol-%), the reaction re-
quired longer reaction times (5 h at room temp.) for com-
pletion and afforded a 36:64 mixture of the same lactones
with 3ЈAa as the major diastereoisomer (Scheme 2).
Crystallization of 3Aa allowed its unequivocal assignment
as the S*,S* isomer by X-ray analysis (see Figure 1).[11]
Table 1. Screening results for the addition of 2a to tropone 1A.[a]
Entry Catalyst
(mol-%)
Solvent
dr[b]
Conversion
[%]
1
2
3
4
5
6
7
8
dpp (5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
HCCl3
toluene
p-xylene
p-xylene
CH2Cl2
70:30
70:30
76:24
73:27[d]
77:23
65:35
71:29
85:15
93:7
100
83
65
98
100
86
90
100
BzOH (5)
TsOH (5)
CSA[c] (5)
TFA (5)
TFA (5)
TFA (5)
TFA (5)
TFA (5)
TFA (1)
TFA (5)
9
10
11
100 (95)[e]
85[f]
25[g, h]
90:10
81:19
[a] All reactions were performed with 1A (0.1 mmol), 2a
(0.12 mmol), and solvent (0.3 mL). [b] Diastereomeric ratio deter-
mined by 1H NMR spectroscopy. [c] Camphorsulfonic acid. [d]
Compound 3Aa was nearly racemic. [e] Combined isolated yield.
[f] Conversion after 24 h. [g] Reaction was performed at 0 °C. [h]
Conversion after 48 h.
Figure 1. Two different views of 3Aa obtained by X-ray analysis.
Scheme 2. Reaction of the tropone 1A with the azlactone 2a under different conditions.
1396
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1395–1400

[8+2] Formal Cycloaddition Reaction of Tropones with Azlactones
%) substantially decreased the reactivity (85% conversion those from alanine (R1 = Me, 2a), norvaline (R1 = nPr,
was observed after 24 h; Table 1, Entry 10), and a decrease 2b), and homophenylalanine (R1 = CH2CH2Ph, 2c), led to
in the reaction temperature (0 °C) slightly improved the dr, lactones 3Aa–3Ac in excellent yields (Ͼ95%) and good dia-
but there was only moderate conversion after 48 h (Table 1, stereoselectivities (Table 2, Entries 1–3). Similar results were
compare Entries 5 and 11).[12]
obtained for the reaction of 1A with the methionine deriva-
Under the best conditions (Table 1, Entry 9), we studied tives 2d (R1 = CH2SCH3, Table 2, Entry 4), 2e (R1
=
the scope of the reaction of 1A with azlactones derived PhCH2, Table 2, Entry 5), 2f (R1 = CyCH2, Table 2, Entry
from different amino acids (2a–2j; Table 2). The reactions 6), and 2g (R1 = iPrCH2, Table 2, Entry 7). The reaction of
with azlactone derivatives with linear alkyl chains, such as 1A with 2h, which bears a bulkier iPr group at the α posi-
tion, also afforded 3Ah (dr up to 94:6) in slightly lower yield
(70%, Table 2, Entry 8). The negative influences of the aryl
Table 2. Scope of the 1,8-nucleophilic addition of different azlact-
groups at C-4 on the stereoselectivity (2i, R1 = Ph, Table 2,
Entry 9) and the alkyl groups at C-2 on the reactivity (2j,
R2 = Me, Table 2, Entry 10) are notable.
ones 2a–2j to the tropone 1A.[a]
The stereoselectivity can be explained by assuming that
a hydrogen bond is initially formed between the OH group
of the enol (which acts as a nucleophile in acidic medium)
and the oxygen atom of the protonated tropone (activated
electrophile).[13] Now, two possible transition states (TS-I
and TS-II, Scheme 3), which differ in the diastereotopic car-
bon atom (C-α in TS-I or C-αЈ in TS-II) that is attacked
by the enol nucleophile, can be postulated. TS-I must be
destabilized with respect to TS-II because of the steric inter-
actions, and this determine the predominance of the S*,S*
isomer in the reaction mixture. The evolution of the re-
sulting intermediates by intramolecular opening of the
azlactone rings affords the lactones 3 (major) and 3Ј.
We hypothesized that the incorporation of a substituent
at the α-position (e.g., Cl) should have a significant influ-
ence on the chemoselectivity because it would produce an
additional destabilization of I (with the Cl/R interaction in-
stead of H/R) without affecting II, which would favor even
more the prevalence of 3 with respect to 3Ј. In addition, the
incorporation of a chlorine atom at the α-position of the
tropone ring would be interesting because its elimination
could generate quaternary amino acids with tropone rings
at C-α. The results obtained in the reactions of the α-
Entry
Azlactone
(R1, R2)
dr[b]
(3/3Ј)
Compound[c]
(yield [%])
1
2
3
4
5
6
7
8
9
2a (Me, Ph)
2b (nPr, Ph)
93:7
93:7
3Aa (95)
3Ab (95)
3Ac (95)
3Ad (98)
3Ae (89)
3Af (76)
3Ag (91)
3Ah (70)
3Ai (92)
3Aj (32)
2c (PhCH2CH2, Ph)
2d (CH3SCH2, Ph)
2e (PhCH2, Ph)
2f (CyCH2, Ph)
2g (iPrCH2, Ph)
2h (iPr, Ph)
88:12
87:13
88:12
81:19
86:14
94:6
2i (Ph, Ph)
2j (Me, Me)
62:38
85:15
10
[a] All reactions were performed with 1A (0.1 mmol) and 2
(0.12 mmol) in xylene (0.3 mL). [b] Diastereomeric ratio deter-
mined by H NMR spectroscopy. [c] Combined isolated yield.
1
Scheme 3. Possible transition states in the reaction of protonated tropones with azlactones.
Eur. J. Org. Chem. 2014, 1395–1400
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1397

J. L. G. Ruano, J. Alemán et al.
FULL PAPER
chlorotropone (1B) with the azlactones 2a, 2b, and 2f–2h
Once we had obtained these dihydro-2H-cyclohepta[b]-
are indicated in Table 3. The reactivity of 1B was lower than furan derivatives 3, we studied their behavior with different
that of 1A, and 24 h was required for full conversion.[14] nucleophiles. The reaction of 3Aa with MeOH/K2CO3 af-
The chemoselectivity was completely controlled, and only forded the α,α-dimethyl cycloheptadienone α-aminomethyl
the diastereomerically pure products 3Ba–3Bj were formed ester 4Aa in only 20 min at –20 °C (88% yield), presumably
as a result of the attack at the unsubstituted αЈ-position. owing to the protonation of the enolate III formed in the
Both facts were expected owing to the previously men- ring-opening reaction (Scheme 4). Similar behavior was ob-
tioned steric repulsion produced by the chlorine atom. Ad- served for the reaction of 3Aa with glycine methyl ester,
ditionally, the S*,S* configuration of 3Ba was unequivo- which afforded 5Aa in good yield (60%).[16]
cally assigned by X-ray analysis (Figure 2),[15] which sup-
ports the mechanism suggested in Scheme 3.
The results obtained in the reaction of the chloro deriva-
tive 3B with different nucleophiles were more interesting
(Table 4). In this case, the product of the nucleophilic open-
ing of the lactone ring is subsequently dehydrohalogenated
with another molecule of the nucleophile acting as a base or
with an external base (K2CO3). The reactions with MeOH,
iPrNH2, and glycine afforded only one α-(2-tropyl), α-alkyl
amino acid derivative (Table 4, Entries 1–3). Homochiral
amino acids gave separable diastereoisomeric mixtures of
enantiomerically pure dipeptides that differed in the config-
uration at the quaternary carbon atom (Table 4, Entries 3–
8).[17] Owing to the lower reactivity of α-substituted amino
acids, we studied different reaction conditions with 1.0 and
4.0 equiv. of the Ala-OBn amino acid and also with an ex-
ternal base (1.0 equiv. of K2CO3). We found higher yields
with 4 equiv. (Table 4, Entries 4 and 6)[18] than with 1 equiv.
Table 3. Scope for the 1,8-Michael addition of different azlactones
2a–2h to the tropone 1B.[a]
Entry Azlactone
(R1, R2)
3/3Ј[b]
Compound
(isolated yield [%])
Table 4. Synthesis of esters and amides from lactones 3B.[a]
1
2
3
4
5
6
2a (Me, Ph)
Ͼ98:Ͻ2
Ͼ98:Ͻ2
Ͼ98:Ͻ2
Ͼ98:Ͻ2
Ͼ98:Ͻ2
Ͼ98:Ͻ2
3Ba (97)
3Ba (98)[c]
3Bb (97)
3Bf (87)
3Bg (93)
3Bh (72)
2a (Me, Ph)
2b (nPr, Me)
2f (CyCH2, Ph)
2g (iPrCH2, Ph)
2h (iPr, Ph)
[a] All reactions were performed with 1B (0.1 mmol) and 2
(0.12 mmol) in p-xylene (0.3 mL). [b] Determined by 1H NMR
spectroscopy. [c] Reaction performed on 1.0 mmol scale.
Entry Nucleophilic reagent
(equiv.)
Products
(isolated yield [%])
1
2
3
4
5
6
7
8
MeOH (1)[b]
iPrNH2 (1)[b]
Gly-OMe (4.5)
Ala-OBn (4)
Ala-OBn (1)
Ala-OBn (4)[b]
PhAla-OBn (4)[b]
Val-OBn (4)
6Ba (95)
7Ba (70)
8Ba (100)
9Ba(43)/9ЈBa(35), (90)[a]
9Ba/9ЈBa(60)[a]
9Ba/9ЈBa(98)[a]
10Ba/10ЈBa(81)[a]
11Ba/11ЈBa(47)[a]
Figure 2. Two different views of compound 3Ba obtained by X-ray
analysis.
[a] Combined yield. [b] 1.0 equiv. of K2CO3 was used.
Scheme 4. Synthesis of esters and amides from lactone 3Aa.
1398
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1395–1400

[8+2] Formal Cycloaddition Reaction of Tropones with Azlactones
(Table 4, Entry 5) and a higher reaction rate when a cobase
(K2CO3) was added. In the case of alanine, we were able to
separate the diastereomeric mixture; therefore, this method-
Acknowledgments
Financial support of this work by the Ministerio de Educación y
ology allows the isolation of optically pure dipeptides (9Ba Ciencia (MEC) (grant number CTQ-2012-12168) and Comunidad
Autónoma de Madrid (programa AVANCAT, grant number
CS2009/PPQ-1634) is gratefully acknowledged. J. A. is grateful for
a Ramón y Cajal contract from the Spanish Government, and R.
A. thanks the Mexican Consejo Nacional de Ciencia y Tecnología
(CONACYT) for a postdoctoral fellowship. A. P. is grateful to the
Spanish Government for a Juan de la Cierva contract. F. Y. thanks
CONACYT and the Dirección General de Apoyo al Personal
and 9ЈBa; Table 4, Entry 4). Other amino acids such as
phenylalanine or valine provided similar results although
with a slightly lower yield for the bulkier valine derivative
(Table 4, Entries 7 and 8).
Conclusions
Académico
– Universidad Nacional Autónoma de México
(DGAPA-UNAM) for a sabbatical fellowship.
We have found a new approach for the synthesis of a
variety of dihydro-2H-cyclohepta[b]furan derivatives by re-
action of tropones and azlactones under Brønsted acid ca-
talysis. They can easily be opened with nucleophiles to form
α,α-disubstituted amino acids (or dipeptides) bearing seven-
membered rings at the quaternary carbon atoms. The use of
homochiral amino acids as nucleophiles provides separable
mixtures of enantiomerically pure α-(2-tropyl), α-alkyl α-
amino acid dipeptides.
[1] For reviews on the chemistry of troponoids, see: a) F. Pietra,
Chem. Rev. 1973, 73, 293; b) S. Ito, Y. Fujise, in: Topics in
Nonbenzenoid Aromatic Chemistry (Eds.: T. Nozoe, R. Breslow,
K. Hafner, S. Ito, I. Murata), Hirokawa, Tokyo, 1977, vol. 2,
p. 91; c) F. Pietra, Acc. Chem. Res. 1979, 12, 132; d) D. Lloyd,
in: Nonbenzenoid Conjugated Carbocyclic Compounds, Elsevier,
Amsterdam, 1984; pp 89–125, p. 126–132; e) T. Asao, M. Oda,
in: Methoden der Organischen Chemie (Houben-Weyl) (Ed.: M.
Regitz), Thieme, Stuttgart, Germany, 1985, vol. 5/2c, p. 710; f)
J. H. Rigby, in: Studies in Natural Products Chemistry, Stereose-
lective Synthesis Elsevier, Amsterdam, 1988, part A, vol. 1, p.
545.
Experimental Section
[2] a) A. E. Greene, M. A. Teixeria, E. Barreiro, A. Cruz, P.
Crabbe, J. Org. Chem. 1982, 47, 2553; b) B. M. Trost, P. R.
Seoane, J. Am. Chem. Soc. 1987, 109, 615; c) R. L. Funk, G. L.
Bolton, J. Org. Chem. 1987, 52, 3174; d) K. S. Feldman, J. H.
Come, B. J. Kosmider, P. M. Smith, D. P. Rotella, M.-J. Wu, J.
Org. Chem. 1989, 54, 92; e) J. H. Rigby, H. S. Ateeq, J. Am.
Chem. Soc. 1990, 112, 6442; f) K. S. Feldman, M.-J. Wu, D. P.
Rotella, J. Am. Chem. Soc. 1989, 111, 6457; g) T. Graening, V.
Bette, J. Neudorfl, J. Lex, H.-G. Schmalz, Org. Lett. 2005, 7,
4317.
[3] a) L. Isakovic, J. A. Ashenhurst, J. L. Gleason, Org. Lett. 2001,
3, 4189; b) P. Li, H. Yamamoto, J. Am. Chem. Soc. 2009, 131,
16628.
[4] See, for example: a) Y. Coquerel, J. P. Deprés, A. E. Greene, J.
Philouze, J. Organomet. Chem. 2002, 659, 176; b) J. H. Rigby,
V. Sainte Claire, Synth. Commun. 2012, 25, 4115.
General Methods: NMR spectra were acquired with a Bruker 300
spectrometer at 300 and 75 MHz for 1H and 13C, respectively.
Chemical shifts are reported in ppm relative to residual solvent
signals (CHCl3, δ = 7.26 ppm for 1H NMR, CDCl3, δ = 77.0 ppm).
13C NMR spectra were acquired in broadband-decoupled mode.
Analytical thin layer chromatography (TLC) was performed by
using precoated aluminium-backed plates (Merck Kieselgel 60
F254), and the plates were visualized by ultraviolet irradiation or
KMnO4 dip. Purification of reaction products was performed by
flash chromatography (FC) with silica gel Merck-60 or Fluorisil®
100–200 mesh. Materials: Commercially available tropones 1A and
1B and chiral phosphoric acids were used without further purifica-
tion. Azlactones 2a, 2c–2f, and 2h–2j were synthesized according
to literature procedures.[19]
[5] a) K. Kumar, A. Kapur, M. P. S. Ishar, Org. Lett. 2000, 2, 787;
b) M. Oda, A. Sugiyama, R. Takeuchi, Y. Fujiwara, R. Miya-
take, T. Abe, S. Kuroda, Eur. J. Org. Chem. 2012, 2231, and
references cited therein.
[6] a) B. M. Trost, P. J. McDougall, O. Hartmann, P. T. Walhen, J.
Am. Chem. Soc. 2008, 130, 14960; b) Y. Du, J. Feng, X. Lu,
Org. Lett. 2005, 7, 1987.
[7] In a similar way, ketene aminals, formed in reactions of hetero-
cyclic carbenes with conjugated aldehydes, react with tropones
to yield bicyclic δ-lactones, presumably by an [8+3] annulation
pathway, see: V. Nair, M. Poonoth, S. Vellalath, E. Suresh, R.
Thirumalai, J. Org. Chem. 2006, 71, 8964.
[8] a) K. G. Jastrzabek, R. Subiros-Funosas, F. Albericio, B. Kole-
sinska, Z. J. Kaminski, J. Org. Chem. 2011, 76, 4506; b) A. R.
Katritzky, E. Todadze, P. Angrish, B. Draghici, J. Org. Chem.
2007, 72, 5794.
[9] For recent reviews of α,α-disubstituted α-amino acids, see: a)
Y. Ohfune, T. Shinada, Eur. J. Org. Chem. 2005, 5127; b) M.
Tanaka, Chem. Pharm. Bull. 2007, 55, 349; c) H. Vogt, S. Bräse,
Org. Biomol. Chem. 2007, 5, 406; for other related reviews, see:
d) C. Nájera, J. M. Sansano, Chem. Rev. 2007, 107, 4584; e) K.
Undheim, Amino Acids 2008, 34, 357; f) J. Clayden, M. Don-
nard, J. Lefranc, D. J. Tetlow, Chem. Commun. 2011, 47, 4624.
[10] For general reviews concerning azlactones, see: a) A.-N. R.
Alba, R. Rios, Chem. Asian J. 2011, 6, 720; b) J. S. Fisk, R. A.
Mosey, J. J. Tepe, Chem. Soc. Rev. 2007, 36, 1432; c) R. A. Mo-
General Procedure for the Synthesis of 3Aa–3Aj and 3Ba–3Bh: To
an ordinary vial charged with azlactone 2 (012 mmol) was added
the corresponding tropone 1A or 1B (0.1 mmol) and TFA (5 mol-
%) in p-xylene (0.3 mL) at room temp. Once the reaction was fin-
ished (as monitored by 1H NMR spectroscopy, usually 5–12 h), the
solvent was eliminated under reduced pressure, and the residue was
directly collected by filtration to afford the pure products.
rac-N-[(3S,3aS)-8-Chloro-3-methyl-2-oxo-3,3a-dihydro-2H-cyclo-
hepta[b]furan-3-yl]benzamide (3Ba): The product was obtained as a
unique diastereoisomer by following the standard procedure with
tropone 1B and azlactone 2a to afford a white solid (97% yield),
m.p. 217–219 °C. 1H NMR (300 MHz, [D6]acetone): δ = 8.52 (br
s, 1 H), 7.92 (dd, J = 3.1, 1.1 Hz, 2 H), 7.59–7.55 (m, 1 H), 7.49–
7.46 (m, 2 H), 6.36 (d, J = 1.8 Hz, 2 H), 6.26–6.22 (m, 1 H), 5.64
(dd, J = 3.9, 2.2 Hz, 1 H), 3.64–3.63 (m. 1 H), 1.83 (s, 3 H) ppm.
13C NMR (75 MHz, [D6]acetone): δ = 174.4, 167.8, 142.7, 133.5,
132.9, 129.5, 129.2, 128.4, 128.1, 128.0, 121.7, 106.4, 59.7, 46.2,
20.3 ppm. HRMS (ESI+): calcd. for C17H14ClNO3 [M + H]+
315.0713; found 315.0721.
Supporting Information (see footnote on the first page of this arti-
cle): Characterization data for all compounds. Copies of the 1H
and 13C NMR spectra for the final products.
Eur. J. Org. Chem. 2014, 1395–1400
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1399

J. L. G. Ruano, J. Alemán et al.
FULL PAPER
sey, J. S. Fisk, J. J. Tepe, Tetrahedron: Asymmetry 2008, 19,
2755. For pioneering work in the organocatalytic field, see: d)
J. Alemán, A. Milelli, S. Cabrera, E. Reyes, K. J. Jørgensen,
Chem. Eur. J. 2008, 14, 10958; e) S. Cabrera, E. Reyes, J.
Alemán, A. Milelli, S. Kobbelgaard, K. A. Jørgensen, J. Am.
Chem. Soc. 2008, 130, 12031. For an excellent recent paper, see:
f) D. Uraguchi, Y. Ueki, A. Sugiyama, T. Ooi, Chem. Sci. 2013,
4, 1308.
[13]
[14]
[15]
Alternatively, the mechanism might involve N-protonation of
the azlactone, which makes enolization and ionization to a neu-
tral (mesoionic) azomethine ylide easier.
This lower reactivity can be improved by increasing the amount
of the catalyst to 20 mol-%, but a decrease in the stereoselecti-
vity was also observed.
CCDC-947015 (for 3Ba) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[11] CCDC-913779 (for 3Aa) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[12] Initial trials with different enantiomerically pure acids were un-
successful in transferring chirality, and only moderate enantio-
meric excesses (up to 15%ee) were found.
[16]
The reaction of the alanine methyl ester with 3Aa resulted only
in decomposition of the tropone after several days of reaction.
[17] Under kinetic resolution conditions (0.6 equiv. Ala-OBn), a
mixture of isomers (ca. 2:1) was formed in reactions of 3Ba but
with lower yield.
[18] The excess amino acid can be quantitatively recovered by using
a SCX column.
[19] S. A. Shaw, P. Aleman, J. Christy, J. W. Kampf, P. Va, E. Vedejs,
J. Am. Chem. Soc. 2006, 128, 925.
Received: November 27, 2013
Published Online: January 2, 2014
1400
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1395–1400